PROJECT SUMMARY The Food and Drug Administration (FDA) was recently granted the authority to regulate the content of nicotine in cigarettes to a ?non-addictive? level; such a reduction could drastically reduce the number of smokers in the United States and improve public health. The smoking population is heterogeneous and it is likely that a subset of smokers will be less responsive to a reduction of nicotine content in cigarettes. Evidence suggests that consumption of densely caloric diets (i.e., foods high in fat or sugar content) and elevated body weight may enhance motivated behaviors. Further, smokers tend to consume densely caloric diets and nicotine suppresses body weight. Therefore, it is likely that body weight and diet are important environmental factors that could modify nicotine reinforcement, particularly in the context of nicotine reduction policy. In human and rat populations, body weight gain diverges after prolonged consumption of a densely caloric diet into distinct populations: obesity-prone (OP) and obesity-resistant (OR). Utilization of selectively bred OP and OR rats allow for the ability distinguish the impact of pre-existing underlying genetic factors from the combination of genetic and environmental factors. Data will be collected using a self-administration paradigm in which OP and OR rats are implanted with intravenous catheters and allowed to make responses to earn infusions of nicotine. Using an innovative rodent model of obese and lean smokers, this application begins to test the novel hypothesis that diet and propensity to develop obesity on a high fat diet are important factors modifying the reinforcing properties of nicotine, which are particularly relevant at low doses of nicotine. The proposed project aims to examine the effect of body weight after prolonged exposure to a high energy diet on: 1) primary nicotine reinforcement; and 2) the contribution of other salient environmental stimuli in nicotine reinforcement. Experiments are designed to test the hypothesis that resistance to develop diet-induced obesity increases responding for the primary reinforcing properties of nicotine, cue-maintained behavior, and the reinforcement enhancing properties of nicotine. 1) Female and male OP and OR rats will be allowed to respond for infusions of nicotine across a range of doses, with the hypothesis that resistance to obesity will decrease the threshold dose for acquisition of stable behavior. 2) The ability of cues to maintain behavior as conditioned reinforcers will be tested in male and female OP and OR rats. These results will be extended to test the impact of diet and body weight on nicotine?s powerful reinforcement enhancing properties. This proposed project will be the first to test nicotine self-administration in a model of human obesity. Collectively, these studies may provide insight regarding strategies for reducing smoking and overall tobacco use in a specific subpopulation of risk.